My research project is to investigate the macromolecular recognition and inhibition between serine proteases and their inhibitors. In particular, I am studying the origin of the broad inhibitory specificity of ecotin, an E. coli protease inhibitor. The goal of this study is to understand the molecular basis of ecotin's inhibitor specificity and introduce novel specificity into ecotin to target disease related serine proteases. Based on the high-resolution crystal structure of trypsin ecotin complex, I have designed a series of ecotin variants at the two loops of ecotin and tested these mutants against different proteases. The result suggests a unique mode of inhibition of ecotin through a secondary binding site that does not occur in other serine protease inhibitors. This finding may lead to novel approaches to design specific protease inhibitors. The molecular modeling of ecotin loop mutants is accomplished with MidasPlus software in CGL.